tbuckley/cabot-search huggingface dataset:
Epithelial presenilin-1 drives colorectal tumour growth by controlling EGFR-COX2 signalling
Authors: Reyes Gamez-Belmonte, Mousumi Mahapatro, Lena Erkert, Miguel Gonzalez-Acera, Elisabeth Naschberger, Yuqiang Yu, Mireia Tena-Garitaonaindia, Jay V Patankar, Yara Wagner, Eva Podstawa, Lena Schödel, Marvin Bubeck, Markus F Neurath, Michael Stürzl, Christoph Becker
Journal: Gut (2022)

Objective Psen1 was previously characterised as a crucial factor in the pathogenesis of neurodegeneration in patients with Alzheimer’s disease. Little, if any, is known about its function in the gut. Here, we uncovered an unexpected functional role of Psen1 in gut epithelial cells during intestinal tumourigenesis. Design Human colorectal cancer (CRC) and control samples were investigated for PSEN1 and proteins of theγ-secretase complex. Tumour formation was analysed in the AOM-DSS and Apc min/+ mouse models using newly generated epithelial-specific Psen1 deficient mice. Psen1 deficient human CRC cells were studied in a xenograft tumour model. Tumour-derived organoids were analysed for growth and RNA-Seq was performed to identify Psen1-regulated pathways. Tumouroids were generated to study EGFR activation and evaluation of the influence of prostanoids. Results PSEN1 is expressed in the intestinal epithelium and its level is increased in human CRC. Psen1 -deficient mice developed only small tumours and human cancer cell lines deficient in Psen1 had a reduced tumourigenicity. Tumouroids derived from Psen1 -deficient Apc min/+ mice exhibited stunted growth and reduced cell proliferation. On a molecular level, PSEN1 potentiated tumour cell proliferation via enhanced EGFR signalling and COX-2 production. Exogenous administration of PGE 2 reversed the slow growth of PSEN1 deficient tumour cells via PGE 2 receptor 4 (EP4) receptor signalling. Conclusions Psen1 drives tumour development by increasing EGFR signalling via NOTCH1 processing, and by activating the COX-2-PGE 2 pathway. PSEN1 inhibition could be a useful strategy in treatment of CRC.
Efficacy and safety of non-pharmacological and non-biological interventions: a systematic literature review informing the 2022 update of the ASAS/EULAR recommendations for the management of axial spondyloarthritis
Authors: Augusta Ortolan, Casper Webers, Alexandre Sepriano, Louise Falzon, Xenofon Baraliakos, Robert BM Landewé, Sofia Ramiro, Désirée van der Heijde, Elena Nikiphorou
Journal: Annals of the Rheumatic Diseases (2022)

Objective To update the evidence of non-biological treatments for axial spondyloarthritis (axSpA), as a basis for the 2022 Assessment of SpondyloArthritis international Society-European Alliance of Associations for Rheumatology (ASAS-EULAR) recommendations for the management of axSpA. Methods A systematic literature review (2016–2021) on efficacy and safety of non-pharmacological and non-biological pharmacological treatments was performed, up to 1 January 2022. The research question was formulated according to the PICO format: Population: adult patients with r-axSpA and nr-axSpA; Intervention: non-pharmacological and non-biological pharmacological treatments; Comparator: active comparator or placebo; Outcomes: all relevant efficacy and safety outcomes. Type of studies included were: randomised controlled trials (RCTs), observational studies (for efficacy of non-pharmacological treatments, and safety), qualitative studies. Cohen’s effect size (ES) was calculated for non-pharmacological and risk ratio (RR) for pharmacological treatments. Results Of 107 publications included, 63 addressed non-pharmacological interventions, including education (n=8) and exercise (n=20). The ES for education on disease activity, function, mobility was small to moderate (eg. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), ES: 0.06–0.59). Exercise had moderate to high ES on these outcomes (eg. BASDAI, ES: 0.14–1.43). Six RCTs on targeted synthetic disease-modifying antirheumatic drugs (DMARDs) showed efficacy of tofacitinib, upadacitinib and filgotinib (phase 2 only) in r-axSpA (range RR vs placebo for ASAS20: 1.91–3.10), while apremilast and nilotinib were not efficacious. Studies on conventional synthetic DMARDs (n=3), non-steroidal anti-inflammatory drugs (NSAIDs, n=8) and other drugs (n=12) did not provide new evidence on efficacy/safety (efficacy of NSAIDs confirmed; limited efficacy of short-term glucocorticoids in one RCT). Conclusions Education, exercise and NSAIDs confirmed to be efficacious in axSpA. JAKi were proved efficacious in r-axSpA.
Prophylactic vaccination against hepatitis D virus superinfection: from fiction to reality?
Authors: Julia Lang-Meli, Christoph Neumann-Haefelin
Journal: Gut (2022)

<h3>Background/aims</h3> The accuracy of pattern deviation (PD) in estimating the damage to the glaucomatous visual field (VF) in the central 10° in eyes with glaucoma and cataract is unclear. <h3>Methods</h3> This retrospective study includes 63 eyes of 52 glaucoma patients who successfully underwent cataract surgery or cataract surgery plus iStent implantation. Using the Humphrey Field Analyser 10–2 test, VF was measured within 6 months preoperatively and postoperatively (VF<sub>pre</sub> and VF<sub>post</sub>, respectively). The mean total deviation values in VF<sub>post</sub> (mTD<sub>post</sub>) indicates glaucomatous damage without cataract and the difference between this value and mean PD values in VF<sub>pre</sub> (mPD<sub>pre</sub>) was evaluated (εmPD). The effect of cataract was then evaluated as the difference between mTD<sub>post</sub> and mTD<sub>pre</sub> (ΔmTD), while the effects of mTD<sub>post</sub> and ΔmTD on εmPD were also assessed. In addition, based on preoperative visual acuity (VA<sub>pre</sub>) and VF<sub>pre</sub>, the optimal model for predicting mTD<sub>post</sub> was identified. The error of this method (εOptimalModel) was estimated as the difference against mTD<sub>post</sub>, which was compared with εmPD. <h3>Results</h3> Compared with mTD<sub>pre</sub>, there was a significant improvement in mTD<sub>post</sub> (p=0.028). A significant difference was observed between mPD<sub>pre</sub> and mTD<sub>post</sub> (p&lt;0.001). Further, εmPD significantly increased with the increase of mTD<sub>post</sub> or ΔmTD (p&lt;0.001 and p=0.0444, respectively). The absolute εOptimalModel was significantly smaller than the absolute εmPD (p&lt;0.001). <h3>Conclusions</h3> This study warns clinicians that PD of the central 10° VF might underestimate the glaucomatous VF damage with the progression of glaucoma and overestimate it as a cataract progresses.
Database of synovial T cell repertoire of rheumatoid arthritis patients identifies cross-reactive potential against pathogens including unencountered SARS-CoV-2
Authors: Zihan Zheng, Ling Chang, Jie Mu, Qingshan Ni, Zhong Bing, Qing-Hua Zou, Ying Wan, Yuzhang Wu, Jingyi Li, Liyun Zou
Journal: Annals of the Rheumatic Diseases (2022)
Mediators of systemic sclerosis-associated interstitial lung disease (SSc-ILD): systematic review and meta-analyses
Authors: Aislin Fields, Koray N Potel, Rhandel Cabuhal, Buena Aziri, Iain D Stewart, Bettina C Schock
Journal: Thorax (2022)

Systemic sclerosis-associated interstitial lung disease (SSc-ILD) is rare, poorly understood, with heterogeneous characteristics resulting in difficult diagnosis. We aimed to systematically review evidence of soluble markers in peripheral blood or bronchoalveolar lavage fluid (BALF) as biomarkers in SSc-ILD.Five databases were screened for observational or interventional, peer-reviewed studies in adults published between January 2000 and September 2021 that assessed levels of biomarkers in peripheral blood or BALF of SSc-ILD patients compared with healthy controls. Qualitative assessment was performed using Critical Appraisal Skills Programme (CASP) checklists. Standardised mean difference (SMD) in biomarkers were combined in random-effects meta-analyses where multiple independent studies reported quantitative data.768 published studies were identified; 38 articles were included in the qualitative synthesis. Thirteen studies were included in the meta-analyses representing three biomarkers: KL6, SP-D and IL-8. Greater IL-8 levels were associated with SSc-ILD in both peripheral blood and BALF, overall SMD 0.88 (95% CI 0.61 to 1.15; I2=1%). Greater levels of SP-D and KL-6 were both estimated in SSc-ILD peripheral blood compared with healthy controls, at an SMD of 1.78 (95% CI 1.50 to 2.17; I2=8%) and 1.66 (95% CI 1.17 to 2.14; I2=76%), respectively.We provide robust evidence that KL-6, SP-D and IL-8 have the potential to serve as reliable biomarkers in blood/BALF for supporting the diagnosis of SSc-ILD. However, while several other biomarkers have been proposed, the evidence of their independent value in diagnosis and prognosis is currently lacking and needs further investigation.CRD42021282452.
Multispectral fluorine-19 MRI enables longitudinal and noninvasive monitoring of tumor-associated macrophages
Authors: Davide Croci, Rui Santalla Méndez, Sebastian Temme, Klara Soukup, Nadine Fournier, Anoek Zomer, Roberto Colotti, Vladimir Wischnewski, Ulrich Flögel, Ruud B. van Heeswijk, Johanna A. Joyce
Journal: Science Translational Medicine (2022)

High-grade gliomas, the most common and aggressive primary brain tumors, are characterized by a complex tumor microenvironment (TME). Among the immune cells infiltrating the glioma TME, tumor-associated microglia and macrophages (TAMs) constitute the major compartment. In patients with gliomas, increased TAM abundance is associated with more aggressive disease. Alterations in TAM phenotypes and functions have been reported in preclinical models of multiple cancers during tumor development and after therapeutic interventions, including radiotherapy and molecular targeted therapies. These findings indicate that it is crucial to evaluate TAM abundance and dynamics over time. Current techniques to quantify TAMs in patients rely mainly on histological staining of tumor biopsies. Although informative, these techniques require an invasive procedure to harvest the tissue sample and typically only result in a snapshot of a small region at a single point in time. Fluorine isotope 19 MRI (19F MRI) represents a powerful means to noninvasively and longitudinally monitor myeloid cells in pathological conditions by intravenously injecting perfluorocarbon-containing nanoparticles (PFC-NP). In this study, we demonstrated the feasibility and power of 19F MRI in preclinical models of gliomagenesis, breast-to-brain metastasis, and breast cancer and showed that the major cellular source of 19F signal consists of TAMs. Moreover, multispectral 19F MRI with two different PFC-NP allowed us to identify spatially and temporally distinct TAM niches in radiotherapy-recurrent murine gliomas. Together, we have imaged TAMs noninvasively and longitudinally with integrated cellular, spatial, and temporal resolution, thus revealing important biological insights into the critical functions of TAMs, including in disease recurrence.
Endotypes of chronic rhinosinusitis based on inflammatory and remodeling factors
Authors: Xiangdong Wang, Yutong Sima, Yan Zhao, Nan Zhang, Ming Zheng, Kun Du, Min Wang, Yue Wang, Yun Hao, Ying Li, Manjiao Liu, Yingshi Piao, Chengyao Liu, Peter Tomassen, Luo Zhang, Claus Bachert
Journal: Journal of Allergy and Clinical Immunology (2022)
Physical and barrier changes in gastrointestinal mucus induced by the permeation enhancer sodium 8-[(2-hydroxybenzoyl)amino]octanoate (SNAC)
Authors: J.S. Mortensen, S.S.-R. Bohr, S. Harloff-Helleberg, N.S. Hatzakis, L. Saaby, H.M. Nielsen
Journal: Journal of Controlled Release (2022)

Drug delivery systems (DDS) for oral delivery of peptide drugs contain excipients that facilitate and enhance absorption. However, little knowledge exists on how DDS excipients such as permeation enhancers interact with the gastrointestinal mucus barrier. This study aimed to investigate interactions of the permeation enhancer sodium 8-[(2-hydroxybenzoyl)amino]octanoate (SNAC) with ex vivo porcine intestinal mucus (PIM), ex vivo porcine gastric mucus (PGM), as well as with in vitro biosimilar mucus (BM) by profiling their physical and barrier properties upon exposure to SNAC. Bulk mucus permeability studies using the peptides cyclosporine A and vancomycin, ovalbumin as a model protein, as well as fluorescein-isothiocyanate dextrans (FDs) of different molecular weights and different surface charges were conducted in parallel to mucus retention force studies using a texture analyzer, rheological studies, cryo-scanning electron microscopy (cryo-SEM), and single particle tracking of fluorescence-labelled nanoparticles to investigate the effects of the SNAC-mucus interaction. The exposure of SNAC to PIM increased the mucus retention force, storage modulus, viscosity, increased nanoparticle confinement within PIM as well as decreased the permeation of cyclosporine A and ovalbumin through PIM. Surprisingly, the viscosity of PGM and the permeation of cyclosporine A and ovalbumin through PGM was unaffected by the presence of SNAC, thus the effect of SNAC depended on the regional site that mucus was collected from. In the absence of SNAC, the permeation of different molecular weight and differently charged FDs through PIM was comparable to that through BM. However, while bulk permeation of neither of the FDs through PIM was affected by SNAC, the presence of SNAC decreased the permeation of FD4 and increased the permeation of FD150 kDa through BM. Additionally, and in contrast to observations in PIM, nanoparticle confinement within BM remained unaffected by the presence of SNAC. In conclusion, the present study showed that SNAC altered the physical and barrier properties of PIM, but not of PGM. The effects of SNAC in PIM were not observed in the BM in vitro model. Altogether, the study highlights the need for further understanding how permeation enhancers influence the mucus barrier and illustrates that the selected mucus model for such studies should be chosen with care.
Remodeling of the osteoimmune microenvironment after biomaterials implantation in murine tibia: Single-cell transcriptome analysis
Authors: Jia Li, Congrui Zhao, Yangbo Xu, Lu Song, Yanqi Chen, Yuzi Xu, Yang Ma, Siyuan Wang, Antian Xu, Fuming He
Journal: Bioactive Materials (2022)

Osseointegration seems to be a foreign body reaction equilibrium due to the complicated interactions between the immune and skeletal systems. The heterogeneity of the osteoimmune microenvironment in the osseointegration of implant materials remains elusive. Here, a single-cell study involving 40043 cells is conducted, and a total of 10 distinct cell clusters are identified from five different groups. A preliminary description of the osteoimmune microenvironment revealed the diverse cellular heterogeneity and dynamic changes modulated by implant properties. The increased immature neutrophils, Ly6C
Advances in orthodontic clear aligner materials
Authors: Yashodhan M. Bichu, Abdulraheem Alwafi, Xiaomo Liu, James Andrews, Björn Ludwig, Aditi Y. Bichu, Bingshuang Zou
Journal: Bioactive Materials (2022)

Rapid technological improvements in biomaterials, computer-aided design (CAD) and manufacturing (CAM) have endorsed clear aligner therapy (CAT) as a mainstay of orthodontic treatment, and the materials employed for aligner fabrication play an all-important role in determining the clinical performance of clear aligners. This narrative review has attempted to comprehensively encompass the entire gamut of materials currently used for the fabrication of clear aligners and elucidate their characteristics that are crucial in determining their performance in an oral environment. Historical developments and current protocols in aligner fabrication, features of contemporary bioactive materials, and emerging trends related to CAT are discussed. Advances in aligner material chemistry and engineering possess the potential to bring about radical transformations in the therapeutic applications of CAT; in the absence of which, clear aligners would continue to underperform clinically, due to their inherent biomechanical constraints. Finally, while innovations in aligner materials such as shape memory polymers, direct three-dimensional (3D) printed clear aligners and bioactive materials combined with clear aligner materials are essential to further advance the applications of CAT; increased awareness of environmental responsibilities among aligner manufacturers, aligner prescribing clinicians and aligner users is essential for better alignment of our climate change goals towards a sustainable planet.
Digital health technology-specific risks for medical malpractice liability
Authors: Simon P Rowland, J. Edward Fitzgerald, Matthew Lungren, Elizabeth Lee, Zach Harned, Alison H. McGregor
Journal: npj Digital Medicine (2022)

Abstract Medical professionals are increasingly required to use digital technologies as part of care delivery and this may represent a risk for medical error and subsequent malpractice liability. For example, if there is a medical error, should the error be attributed to the clinician or the artificial intelligence-based clinical decision-making system? In this article, we identify and discuss digital health technology-specific risks for malpractice liability and offer practical advice for the mitigation of malpractice risk.
Replication stress generates distinctive landscapes of DNA copy number alterations and chromosome scale losses
Authors: Nadeem Shaikh, Alice Mazzagatti, Simone De Angelis, Sarah C. Johnson, Bjorn Bakker, Diana C. J. Spierings, René Wardenaar, Eleni Maniati, Jun Wang, Michael A. Boemo, Floris Foijer, Sarah E. McClelland
Journal: Genome biology (2022)

Abstract Background A major driver of cancer chromosomal instability is replication stress, the slowing or stalling of DNA replication. How replication stress and genomic instability are connected is not known. Aphidicolin-induced replication stress induces breakages at common fragile sites, but the exact causes of fragility are debated, and acute genomic consequences of replication stress are not fully explored. Results We characterize DNA copy number alterations (CNAs) in single, diploid non-transformed cells, caused by one cell cycle in the presence of either aphidicolin or hydroxyurea. Multiple types of CNAs are generated, associated with different genomic regions and features, and observed copy number landscapes are distinct between aphidicolin and hydroxyurea-induced replication stress. Coupling cell type-specific analysis of CNAs to gene expression and single-cell replication timing analyses pinpointed the causative large genes of the most recurrent chromosome-scale CNAs in aphidicolin. These are clustered on chromosome 7 in RPE1 epithelial cells but chromosome 1 in BJ fibroblasts. Chromosome arm level CNAs also generate acentric lagging chromatin and micronuclei containing these chromosomes. Conclusions Chromosomal instability driven by replication stress occurs via focal CNAs and chromosome arm scale changes, with the latter confined to a very small subset of chromosome regions, potentially heavily skewing cancer genome evolution. Different inducers of replication stress lead to distinctive CNA landscapes providing the opportunity to derive copy number signatures of specific replication stress mechanisms. Single-cell CNA analysis thus reveals the impact of replication stress on the genome, providing insights into the molecular mechanisms which fuel chromosomal instability in cancer.
Computational quantification and characterization of independently evolving cellular subpopulations within tumors is critical to inhibit anti-cancer therapy resistance
Authors: Heba Alkhatib, Ariel M. Rubinstein, Swetha Vasudevan, Efrat Flashner-Abramson, Shira Stefansky, Sangita Roy Chowdhury, Solomon Oguche, Tamar Peretz-Yablonsky, Avital Granit, Zvi Granot, Ittai Ben-Porath, Kim Sheva, Jon Feldman, Noa E. Cohen, Amichay Meirovitz, Nataly Kravchenko-Balasha
Journal: Genome Medicine (2022)

Abstract Background Drug resistance continues to be a major limiting factor across diverse anti-cancer therapies. Contributing to the complexity of this challenge is cancer plasticity, in which one cancer subtype switches to another in response to treatment, for example, triple-negative breast cancer (TNBC) to Her2-positive breast cancer. For optimal treatment outcomes, accurate tumor diagnosis and subsequent therapeutic decisions are vital. This study assessed a novel approach to characterize treatment-induced evolutionary changes of distinct tumor cell subpopulations to identify and therapeutically exploit anticancer drug resistance. Methods In this research, an information-theoretic single-cell quantification strategy was developed to provide a high-resolution and individualized assessment of tumor composition for a customized treatment approach. Briefly, this single-cell quantification strategy computes cell barcodes based on at least 100,000 tumor cells from each experiment and reveals a cell-specific signaling signature (CSSS) composed of a set of ongoing processes in each cell. Results Using these CSSS-based barcodes, distinct subpopulations evolving within the tumor in response to an outside influence, like anticancer treatments, were revealed and mapped. Barcodes were further applied to assign targeted drug combinations to each individual tumor to optimize tumor response to therapy. The strategy was validated using TNBC models and patient-derived tumors known to switch phenotypes in response to radiotherapy (RT). Conclusions We show that a barcode-guided targeted drug cocktail significantly enhances tumor response to RT and prevents regrowth of once-resistant tumors. The strategy presented herein shows promise in preventing cancer treatment resistance, with significant applicability in clinical use.
GATA4 Regulates Developing Endocardium Through Interaction With ETS1
Authors: Pingzhu Zhou, Yan Zhang, Isha Sethi, Lincai Ye, Michael A. Trembley, Yangpo Cao, Brynn N. Akerberg, Feng Xiao, Xiaoran Zhang, Kai Li, Blake D. Jardin, Neil Mazumdar, Qing Ma, Aibin He, Bin Zhou, William T. Pu
Journal: Circulation Research (2022)

The pioneer transcription factor (TF) GATA4 (GATA Binding Protein 4) is expressed in multiple cardiovascular lineages and is essential for heart development. GATA4 lineage-specific occupancy in the developing heart underlies its lineage specific activities. Here, we characterized GATA4 chromatin occupancy in cardiomyocyte and endocardial lineages, dissected mechanisms that control lineage specific occupancy, and analyzed GATA4 regulation of endocardial gene expression.